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![So what’s a drug ?
Drug describes [any] articles intended for use in
the diagnosis, cure, mitigation, treatment, or
prevention of disease in man or other animals.
15](https://image.slidesharecdn.com/fdaapplicationsinanutshell-141021085414-conversion-gate01/75/FDA-applications-in-a-nutshell-15-2048.jpg)
![What is a “new” drug
• The regulatory definition of "new drug“ is critical as it establishes
both the need for, and requirements for approval
A Ne • New Drug is an active substance which is not generally
recognized, among experts qualified to evaluate the safety and
effectiveness of drugs (FDA), as safe and effective for use under
the conditions prescribed, recommended, or suggested in the
labeling thereof
• Approved via IND/NDA
• Active compounds recognized under the Food and Drugs Act of
June 30, 1906 are the exception [“Old Drug”]
16](https://image.slidesharecdn.com/fdaapplicationsinanutshell-141021085414-conversion-gate01/75/FDA-applications-in-a-nutshell-16-2048.jpg)
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Similar to FDA applications in a nutshell
FDA applications in a nutshell
- 1. FDA Applications ina Nutshell
- 2. “Good science andgood regulatory practice often part company” …..* *(sometimes..) park the science and follow the rules
- 3. Some Thoughts on“FDA in a nutshell” (??) •• Perceived as Formulaic … • In Reality – Program Specific – Remains Subject to Change – Often unpredictable – Risky – Subject to “intangibles” – Failure prone
- 4. Development Landscape •Biopharma development – among the most highly regulated of any commercial activity • Sheer Number of Regulations = complexity • Even well- run, and compliant programs fail • Program risk has discouraged innovation • Understanding the intangibles mitigates risk
- 5. Changing Scope ofDevelopment • Pharmaceutical development is now conducted to facilitate GLOBAL approval – Pharmaceutical products are “similarly” regulated in essentially every country. – Most countries have their own health authorities with individual “personalities” – Regulations are applicable to both the investigation and marketing of compounds. Intangibles a critical facet of complexity 5
- 6. Drug Development is(deceptively) formulaic • Find a compound with activity • Chemically define it (characterize) •• Explore its basic pharmacology and toxicology • Define safety and efficacy via clinical research • Develop a dosage form • Compile data and file for approval • Wait patiently.. Same formula for years --- why study and strategize the process 6
- 7. Regulatory Framework •Regulations are complex systems of interrelated rules • Govern both development and post approval activities • Continuously undergoing amendment and supplementation • Intended to assure that products are safe (do no harm) and effective ( do some good) •• Most have arisen from adversity 7
- 8. US Base Standardsfor Drugs / Biopharmaceutic Approval • Products must be recognized as safe •• Product must be demonstrated to be effective – 2 adequate and well controlled trials • Benefits of use must always outweigh potential risk • Identified risks must be mitigated 8
- 9. Why we (over)Regulate • All Regulation grew out of adversity – Proven Safety counters impure, adulterated, unsafe • Elixir of Sulfanilamide • Thalidomide – Proven Efficacy counters worthless ““cure alls”” • Snake oil • Medicine shows
- 10. Development Metrics •1 in 1000 candidates make it to phase 1 clinical trial • 8 to 15 years to develop a new drug/biologic product • $802 million spent before the medicine is available for sale • When failures are factored in (not a rare occurrence), Avg. costs exceeds $ 5 billion per drug • 2012 :Nature Reviews Drug Discovery –– Number of drugs invented per billion dollars of R&D reduced by half every 9 years • Attention to early development, successful execution of significant clinical studies helps to reduce number of development failures. 10
- 11. Approval Outcomes andCosts • 400+ Medications Approved in 2000 -2012 • 35 Approved in 2012 • Current Development Time: 10 – 15 years • Medicines in Development – 1999 – 1,800 – 2009 – 2,900 – 2013 - 3,400 – 40% increase since 2005 • Total Development Costs ($), factoring failure – 1975 – 138 mio – 1987 – 318 mio – 2001 – 802 mio – 2006 – 1.318 billion – 2012 – 5.0 billion 11
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- 14. Drug Development: ChangingLandscape To Reduce Risk • Targeted • Outcome / patient focused – Defined Outcome – Best Population – Measurable effect – TRUE Clinical Effectiveness – Anticipated Risk / Benefit – Mitigated Risks • US Approvals Up in 2011 & 2012 – Most approved first pass – Application Quality = Shared Sponsor execution • FDA Remains unpredictable -- Congressional Oversight remains high
- 15. So what’s adrug ? Drug describes [any] articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals. 15
- 16. What is a“new” drug • The regulatory definition of "new drug“ is critical as it establishes both the need for, and requirements for approval A Ne • New Drug is an active substance which is not generally recognized, among experts qualified to evaluate the safety and effectiveness of drugs (FDA), as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof • Approved via IND/NDA • Active compounds recognized under the Food and Drugs Act of June 30, 1906 are the exception [“Old Drug”] 16
- 17. Development Gating –Best Practice low “probability of success” compounds get “pushed along” by inertia To mitigate this risk candidate compounds are typically “gated” Pre-specified criteria are established to prevent blindly moving products along
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- 19. Gated Approaches toRegulated Development • Target Identification • IND Enabling Activities •• IND Filing • NDA Filing • Postapproval Actions
- 20. Candidate Definition –General Investigational Plan A Priori…. •• Define intended Indication • Define target population • Determine Optimal Dosage form • IP / Exclusivity Assessment • Develop Global Regulatory Strategy
- 21. Strategic Approaches toDevelopment • Target Identification – Clinically meaningful – Commercially attractive – Measurable effect
- 22. Initiation of clinicalinvestigation of Target Virtually everything is hinged off clinical studies Problem: How to administer an unapproved drug to a human for testing • US: IND – Investigational New Drug (Application) • EU: CTA – Clinical Trial Authorization 22
- 23. IND Defined •IND - Investigational New Drug (Application) – Documentation submitted to and accepted by FDA before new drug can be shipped interstate for human testing. –– IND includes all evidence that studies can be done with reasonable safety to subject/patient. – Following initial filing, becomes repository for all subsequent amendments, protocols, preclinical/ clinical data • CTA - Clinical Trial Application – EU version of US IND 23
- 24. So…When do Ineed an IND • New Drug • Old Drug –New indication •• New Patient population • New manner of use significantly different from the approved label
- 25. Strategic Approaches toDevelopment • Target Identification – Clinically meaningful – Commercially attractive • I–NMeDasu raEble neffeact bling Activities – Preclinical Pharmacological Characterization – Proof of Concept – Preclinical Tox Characterization – Proof of Safety –Chemistry and Manufacturing – Clinical Development Plan – PK Characterization – Metabolism, Fate – Target Indication Definition • Measure
- 26. IND Development: DrugSubstance - API • Synthesis • Reliable supply •• Quality of Supply – Reproducibility • Stability • Impurities
- 27. IND Development :Preclinical Pharmacology • Proof of Concept • Mechanism of Action •• Target • Characterisation of possible “class”off target effects • Absorbtion • Distribution • Metabolism • Excretion
- 28. IND Development :Preclinical Toxicology • Genotox • Cellular Toxicities •• Whole Animal Studies • Tox Characterisation of major impurities and metabolites • Threshold toxicity to enable investigational study (i.e.
- 29. Gating: Filing Readiness- IND • You have a compound with a justified proof of concept •• You have conducted the minimal required animal toxicology testing • You have a dosage form that is chemically characterized • The dosage form has demonstrated stability for the proposed duration of initial clinical testing • To initiate testing of safety and efficacy in humans..you need to open an IND….
- 30. Strategic Approaches toDevelopment • Target • (Pre-IND Meeting) • IND Filing – Chemical Characterization (API, DPI) to support Clinical Development – Protocol/Investigator/Clinical Development Plan – Phase 1 : Gross Safety – Phase 2 : Dose Finding / Optimization – Phase 3 : Pivotal Trials (2) • Measure
- 31. IND Support: Initiationof Clinical (Trials) • Enabling work Complete • IND filed and “may proceed” •• Clinical Dosage Form Developed • Stability Consistent with longest proposed trial • Clinical packaging • Clinical Trials – Phase 1 – Phase 2 – Phase 3 – Phase 4
- 32. Clinical Research Basics • Clinical Development Plan (volatile..) – Established Protocol – Qualified Investigator – Prospective Analysis Plan…. • Phase 1: safety of product in small numbers of healthy volunteers (n=20-80) • Phase 2: efficacy and safety in small number of patients with target indicated condition – dose range finding (n =100 – 300) • Phase 3: Pivotal market enabling trials – Safety and efficacy compared to PBO and/or standard of care (n = 1,000 – 3,000) • Phase 4: Postmarketing Studies
- 33. A word onendpoints • Proper choice of endpoint (or outcome measured following intervention) is PIVOTAL • A primary efficacy endpoint must be something that has a substantial impact on the course of the target disease, and the patient’’s well-being • There needs to be a validated way to measure this outcome
- 34. Clinical Stage Gating • Phase 1 – no untoward effects, acceptable kinetics •• Phase 2 – Supports dose selection • Phase 3 – Supports S&E in endpoints related to intended indication, and in target patient population
- 35. Pre NDA •CMC full scale up and final production process validation •• Container / Closure • Shelf life supporting stability • Proposed labeling • Agreement on data sets to be presented and manner of presentation
- 36. Strategic Approaches toDevelopment • NDA Filing – Chemistry / Manufacturing Scale Up –– Preclinical Analyses – Clinical Analyses (safety, efficacy) – Integrated Analysis -- Labeling • Postapproval Actions – Risk Mitigation – Post approval Measure
- 37. Marketing Approval Applications • MAA – Marketing Authorization Application - EU – Registration documents seeking approval to market a drug product Ex-US. A general term for registration document. In EU, the MAA implies a document used for multi-national submission as opposed to seeking approval in one specific country. • NDA – New Drug Application - USA – Registration document seeking approval to market a drug product (NOT biological product). • BLA – Biological License Application – USA – Think NDA for a biological drug product. – Heavily focused on process 37
- 38. Marketing Approval Applications US • NDA – New Drug Application – 505(b)(1), – 505(b)(2), – 505(j) ANDA - Abbreviated New Drug Application •• BLA – Biologic License Application EU • MAA – Marketing Authorization Application • CTD – Common Technical Document; – Harmonized common format for organization of information in marketing authorization (registration) applications. 38
- 39. Endgame: Label Development • Label—The label is the document physically attached directly to the packaging materials that are in direct contact with the excipient, drug substance, or drug product. • Labeling—Labeling includes the label and the documents included with, but not attached to, the packaging materials that are in direct contact with the excipient, drug substance, or preparation (e.g., package insert). Label and labeling define the claims made for the drug product in terms of the target for use and the intended patient population It is directly substantiated by the integration of all clinical data 39
- 40. Strategic Approaches toDevelopment • Target Identification – Analysis -- Labeling • Postapproval Actions – Risk Mitigation – Post approval Measure
- 41. Schematic of FDADevelopment and Review
- 42. NDA Review StepsSimplified • Preclinical (animal) testing is completed. • API and DP is initially characterized • Pre IND Meeting held. • Investigational new drug application (IND) supports initiationof human testing in clinical trials. • Chemistry and Manufacturing is further characterized • Pre-NDA meeting held • NDA Submission • NDA Acceptance -- FDA has 60 days to decide whether to file it so it can be reviewed. • FDA “files” the NDA, an FDA review team is assigned • The FDA reviews S/E information and adjudicates to proposed professional labeling • The FDA inspects the facilities where the drug will be manufactured • FDA approves application, or issue a complete response letter.
- 43. Bumps in theRoad If FDA review supports the benefits of a drug outweigh the known risks, the drug will receive approval. Common impediments: • Unexpected safety issues • Failure to demonstrate effectiveness. • Need additional studies--more people, different types of people, a longer period of time. • Manufacturing issues. • Drug for clinical trials does not match market product. • Scale up, supplier or quality control issues • MOST OFTEN a combination of problems that prevent approval. FDA outlines the justification for its decision in a complete response letter to the drug sponsor.
- 44. Remember the intangibles… • Drug /Biotech Development requires cutting edge science, but that’s not all its about • Regulation is supported by science, but science and g pp y , l ti regulation ft often part t company • Industry and academic groups lead (and precede) regulation • Novelty lowers hurdles for approval, but often complicates review process • Product is defined (both) by its active, and the associated claims of action • Product needs to have a meaningful clinical effect • Burden of proof is always on the sponsor • Never, Ever, Forget the value of Regulator relationship 44
- 45. Thoughts on InnovationBreakdown • Promising drugs are not being developed because of the expense and risk of developing them. •• Promising acquisitions are not made because of unacceptable/ un-evaluable Regulatory Risk • The promise of great candidate products is being obscured by focus of their presentation • FDA is unpredictable and risk averse
- 46. Thoughts on InnovationBreakdown • The only way to promote innovation is to de-risk development •• This will require new approached to – Target Choice – Testing Standards – Data Collection – Evaluation • A “disruptive” approach to “de-Risk”
- 47. Innovation Risk influencesValue Inflection Points Development Stage Acquisition Cost • Discovery • $ • Proof of Concept • $$ • First in Human • End of Phase 2 • Pre-NDA • $$$ • $$$$ • $$$$$ • Post Approval • $$$$$$$$$$
- 49. "It must beconsidered that there is nothing more difficult to carry out, nor more doubtful of success nor dangerous to handle, than to initiate a new order of things. Niccolo Machiavelli, 1513